AMNA HASSAN ROLL NO : 12 Chapter : 25Molecular biology of the host microbe interaction in periodontal disease
Topics outline1 . I N N AT E I M M U N I T Y ADAPTIVE IMMUNITY PAT H O B I O LO G Y O F P E R I O D O N TA L DISEASE HOST CELL SIGNALING
INTRODUCTION Provides an overview of molecular biology of the host-parasiterelationship Deals with the microbiota associated LPS and other MAMPs,innate responses,tLRs signaling and periodontal pathogenesis Includes pathobiology of periodontal disease Induction of disease by pro inflammatory cytokines
PATHOGENESIS OUTLINE Direct recognition of microbes by the host is mediated by therecognition of MAMPs by PPR It requires expression of number of bioactive agents i.e. proinflammatory and anti inflammatory cytokines , growth factors andenzymes Activated Biologic mediators are involved in the induction ofadaptive immunity
INNATE IMMUNITY Innate immunity is rapidly activated with in minutes Responsible for the defiance during initial hours and days of infection Challenge is to discriminate among a large number of periodontal pathogen from the host with a limited number of cell surface receptor
H OW I N N AT E I M M U N E SYST E M FUNCTIONS? The discovery of TLRs proved to b critical for recognition ofmicrobes. With in the periodontal tissues , the expression of various TLRsappears to b increased in severe diseased states TLR are a type of PRR ( pattern recognition receptor) EggTLR1,TLR2,TLR3.TLR4. etch
CONTD.. PPR can b secreted into plasma as humoral protein others are localized in the cytoplasm as intracellular sensors Soluble PRR include collectins,ficolins and acute phasepentraxins (e.g. C reactive protein) The soluble mannose binding receptors can interact withstructures and activate complement system
Other receptors are :1. NOD proteins Nod1 recognizes meso-DAP peptidoglycan in most gram – ve and +ve Nod2 recognizes MDP ,found in both gram –ve and +ve
Receptors not only recognize various MAMPs to activateINNATE RESPONSE but they also have a role in inflammation andadaptive responses. Other cells also play important role and respond by expressingbiologically active molecules such as cytokines n MMPs which willeffect homeostasis of host tissue in periodontal environment
CELLS INVOLVED Macrophages & PMNs as phagocytes Dendritic cells as antigen presenting cellsNatural killer cells that recognizes n kill host cells
Fibroblast and • Produce IL -6 osteoblasts ,prostaglandin E2,MMPs. And RANKL Work as a physical barrier, equippedEPITHELIAL CELLS with PRR and respond to MAMPs by secreting cytokines and chemokines
Commensals bacteria such as Streptococcus gordonii orstreptococcus sanguinis induce expression of antimicrobialpeptides without expression of IL 8 Periodontopathogenic bacteria from the ORANGE BACTERIAsuch as Fusobacterium nucleatum and Prevotella intermediainduce strong expression of both anti microbial and IL -*8
RED COMPLEX ORGANISM such as Ttreponema denticola,Tannerella forsythia, Porphyromonas gingivalis suppress theimmune response by inhibiting anti microbial peptides and IL -8 orboth.
C E L L U L A R S I G N A L I N G I N I N N AT E I M M U N I T Y RESPONSE MAMPs get recognize by PRR as a result signal is initiated ->signal is transduced through cytoplasm and nucleus -> posttransitional modifications take place --- determine the cellresponse to MMAPs Recognition of a ligand by TLR-- signals generated usepathways similar to IL 1 receptors .
ADAPTIVE IMMUNITY Innate immunity plays a role in initiating and modulatingadaptive immune responses Innate immune mechanisms are not turned off once theadaptive responses is activated Cells from adaptive immune response also express PRRs andrespond to MAMPs
The adaptive immune response is characterized by the activities ofpathogen-specific B and T lymphocytes the cell type primarily responsible for translating innate signals intoadaptive immunity is the dendritic cell (DC). adaptive immunity initiates with DCs recognizing MAMPs in the sites of infection then subs migrating into the regional draining lymph nodes It then present the processed antigen peptides in the context of major histocompatibility complex (MHC) molecules to naive T lymphocytes
in periodontal diseases, both MAMPs and inflammatorycytokines are usually present to fully activate the DCs, whichsuggests that there is no impairment to a competent activation ofadaptive immunity.
H O ST M I C RO B E I N T E R AC T I O N S DCs activated by MAMPs and inflammatory cytokines (also induced by MAMPs ininnate immune/resident cells) will initiate an adaptive immune response by drivingnaive T lymphocytes into a CD8+ (for cytotoxic response) or CD4+ with Th1 orTh2 phenotypes. more pieces have been added to the puzzle, including the regulatory Tlymphocytes (Tregs), which appear to have their inhibitory functions suppressed byactivated DCs. Activated T cells and their “specific” cytokine profiles will modulate theinflammatory response and also the activation of B lymphocytes.
PAT H O B I O L O G Y O F P E R I O D O N TA L DISEASE Host response to periodontal expression of various proinflammatory and anti inflammatory cytokines, growth factors andenzymes that are the result of activation of multiple signalingpathways PPR signaling is the most important interface between the hostand the microbes
C Y T O K I N E S A N D M E D I AT O R S O F I N F L A M M AT I O N Local inflammatory reaction is characterized by an initialincrease in blood flow , enhanced vascular permeability , andinflux of cell from blood to crevice For acute and rapid defense the mediators involved are1. Histamine2. Bradykinin3. PGE2 and nitrous oxide
Once activated by cytokines, bioactive molecules , and MAMPs,infiltrating cells produce other inflammatory cells that modulatethe activity of other cells Pro inflammatory : LIF Cytokines include are : IL- ,IFN-,CNTF ,TGFb ,GM- Ccytkines include 1@,IL-1b,IL -6 ant TNF@ CSF,IL-11,IL-12,IL-17,IL- 18,IL-8
Anti inflammatory are : IL-4,IL-10,IL-13,IL- 16,INF-@,IL-1Ra etc
A characteristic type of cytokine profile is associated with each type ofperiodontal disease ( gingivitis or periodontitis) Once immune and inflammatory processes are initiated and complex cytokines network is established ,inflammatory molecules play a direct role in degradation of both mineralized and non mineralized tissues of periodontium
R O L E O F R A N K L I N P E R I O D O N TA L DISEASE Rankl plays a pivotal role in bone response since it is involved inosteoclast differentiation , activation and survival As periodontal disease progresses - collagen fibres &connective tissue attachment to tht tooth is destroyed ---junctional epithelial cells proliferate apically along the root surface---- CLINICALLY seen as ATTACHMENT LOSS
E.g. : MMPs released from different cell lesions --- capable ofdegrading all components of ECM MMPs increases with inflammation and disease activity Detection in saliva is a host response bio marker of periodontaldisease
CONTD… RANKL is secreted by fibroblasts ,osteoblast, chondrocytes,mesenchymal cells and T and B lymphocytes. • OPG is the endogenous inhibitor of RANKL • It functions as its decoy receptor • Secreted by osteoblastic cells ,bone marrow stromal cells and fibroblast
The ratio between RANKL and OPG is the currentparadigm for modulation of coupled bone turnover andspecifically in periodontal disease Patients with advanced periodontitis presents with highlevel of RANKL.
Based on susceptibility analysis ,individualdifference in the host response to MAMPs and to host derived cytokines that are the result ofgenetic variations may also play important role in modulating the pathogenesis of periodontal disease
CELL SIGNALING EVENTS1. Production of cytokines and inflammatory mediators is usually a tightly controlled that is initiated by external stimuli>2. Signals are rapidly transduced through the cytoplasm into thenucleus ----gene expression === DNA transcription3. Final assembly of biologically active protein there a greatnumber of regulatory mechanism
T H E R A P E U T I C ST R AT EG I ES Strategies have develop to target the host response to LPSmediated tissue destruction Doxycycline Scaling root planning Surgical therapy MMP inhibitors TNF & IL -1 antagonist